title: Effect of cytokine interplay on macrophage polarization during chronic pulmonary infection with Cryptococcus neoformans.
abstract: The immune response to Cryptococcus neoformans following pulmonary infection of C57BL/6 wild-type (WT) mice results in the development of persistent infection with characteristics of allergic bronchopulmonary mycosis (ABPM). To further clarify the role of Th1/Th2 polarizing cytokines in this model, we performed kinetic analysis of cytokine responses and compared cytokine profiles, pathologies, and macrophage (Mac) polarization status in C. neoformans-infected WT, interleukin-4-deficient (IL-4(-/-)), and gamma interferon-deficient (IFN-γ(-/-)) C57BL/6 mice. Results show that cytokine expression in the infected WT mice is not permanently Th2 biased but changes dynamically over time. Using multiple Mac activation markers, we further demonstrate that IL-4 and IFN-γ regulate the polarization state of Macs in this model. A higher IL-4/IFN-γ ratio leads to the development of alternatively activated Macs (aaMacs), whereas a higher IFN-γ/IL-4 ratio leads to the generation of classically activated Macs (caMacs). WT mice that coexpress IL-4 and IFN-γ during fungal infection concurrently display both types of Mac polarization markers. Concurrent stimulation of Macs with IFN-γ and IL-4 results in an upregulation of both sets of markers within the same cells, i.e., formation of an intermediate aaMac/caMac phenotype. These cells express both inducible nitric oxide synthase (important for clearance) and arginase (associated with chronic/progressive infection). Together, our data demonstrate that the interplay between Th1 and Th2 cytokines supports chronic infection, chronic inflammation, and the development of ABPM pathology in C. neoformans-infected lungs. This cytokine interplay modulates Mac differentiation, including generation of an intermediate caMac/aaMac phenotype, which in turn may support chronic "steady-state" fungal infection and the resultant ABPM pathology.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Arora
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Tsang
authors.forename: Roderick A
authors.initials: RA
authors.lastname: McDonald
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Gary B
authors.initials: GB
authors.lastname: Huffnagle
mesh_terms: D000818:Animals; D003453:Cryptococcosis / Q000276:immunology* / Q000473:pathology; D003455:Cryptococcus neoformans / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000172:deficiency; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D015847:Interleukin-4